Losing the sugar coating: Potential impact of perineuronal net abnormalities on interneurons in schizophrenia

Abstract

Perineuronal nets (PNNs) were shown to be markedly altered in subjects with schizophrenia. In particular, decreases of PNNs have been detected in the amygdala, entorhinal cortex and prefrontal cortex. The formation of these specialized extracellular matrix (ECM) aggregates during postnatal development, their functions and association with distinct populations of GABAergic interneurons, bear great relevance to the pathophysiology of schizophrenia. PNNs gradually mature in an experience-dependent manner during late stages of postnatal development, overlapping with the prodromal period/age of onset of schizophrenia. Throughout adulthood, PNNs regulate neuronal properties, including synaptic remodeling, cell membrane compartmentalization and subsequent regulation of glutamate receptors and calcium channels, and susceptibility to oxidative stress. With the present paper, we discuss evidence for PNN abnormalities in schizophrenia, the potential functional impact of such abnormalities on inhibitory circuits and, in turn, cognitive and emotion processing. We integrate these considerations with results from recent genetic studies showing genetic susceptibility for schizophrenia associated with genes encoding for PNN components, matrix-regulating molecules and immune system factors. Notably, the composition of PNNs is regulated dynamically in response to factors such as fear, reward, stress, and immune response. This regulation occurs through families of matrix metalloproteinases that cleave ECM components, altering their functions and affecting plasticity. Several metalloproteinases have been proposed as vulnerability factors for schizophrenia. We speculate that the physiological process of PNN remodeling may be disrupted in schizophrenia as a result of interactions between matrix remodeling processes and immune system dysregulation. In turn, these mechanisms may contribute to dysfunction of GABAergic neurons.

Catecholaminergic neuronal network dysfunction in the frontal lobe of a genetic mouse model of schizophrenia

“…TH-positive fibres are considered to be a constitutive part of the interneuronal circuits within the frontal cortex. In previous studies, it was suggested that a deficit of interneurons in the frontal cortex; that is, a neuronal network deficit, might be one of the pathogenic mechanisms responsible for schizophrenia (19). In this study, we did not detect any gender-dependent differences in the density of TH-positive fibres in the frontal cortex, which disagrees with the findings of previous studies.…”

Reduced Labeling of Parvalbumin Neurons and Perineuronal Nets in the Dorsolateral Prefrontal Cortex of Subjects with Schizophrenia

“…Most cortical PV neurons, and a small number of PCs, are ensheathed by perineuronal nets (PNNs), a condensed form of extracellular matrix (Berretta et al, 2015) involved in the closure of developmental critical periods, regulation of synaptic plasticity, and are altered by oxidative stress (Cabungcal et al, 2013b;McRae and Porter, 2012). Several PNN proteoglycans, the lecticans, are highly glycosylated, and one, aggrecan, is highly enriched in mature PNNs (Bitanihirwe and Woo, 2014).…”

Perineuronal nets labeled by monoclonal antibody VC1.1 ensheath interneurons expressing parvalbumin and calbindin in the rat amygdala

“…They were initially described by Camillo Golgi using his Golgi technique (Golgi, 1893; Celio and Blümke, 1994; Celio et al, 1998). Investigations conducted in the last 25 years have shown that PNNs consist of a variety of glycoconjugates including hyaluronic acid, proteoglycans, and glycoproteins (Galtrey and Fawcett, 2007; Berretta et al, 2015; Smith et al, 2015). Recent studies have demonstrated that PNNs are formed during postnatal development and are critical for the regulation of a variety of synaptic functions including synaptic stabilization and synaptic plasticity (Galtrey and Fawcett, 2007; Berretta et al, 2015).…”

“…Investigations conducted in the last 25 years have shown that PNNs consist of a variety of glycoconjugates including hyaluronic acid, proteoglycans, and glycoproteins (Galtrey and Fawcett, 2007; Berretta et al, 2015; Smith et al, 2015). Recent studies have demonstrated that PNNs are formed during postnatal development and are critical for the regulation of a variety of synaptic functions including synaptic stabilization and synaptic plasticity (Galtrey and Fawcett, 2007; Berretta et al, 2015). The finding that PNNs and other components of the extracellular matrix are altered in several neurological and neuropsychiatric diseases suggests that a greater understanding of their structure and function could lead to novel therapies to treat these disorders (Viapiano and Matthews, 2006; Galtrey and Fawcett, 2007; Berretta et al, 2015; Maeda, 2015; Smith et al, 2015; Pantazopoulos and Berretta 2016; Sorg et al, 2016).…”